Diapositiva 1

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Highlights in the Management of Breast Cancer
Consorzio Interuniversitario Nazionale per la
Bio-Oncologia (CINBO)
Mediterranean School of Oncology (MSO)
Direttori Prof. Angelo Raffaele Bianco  e  Prof.
Giorgio Mustacchi
Roma 4-5 Luglio 2008
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Azienda Ospedaliero-Universitaria
Cagliari-Monserrato
Do micrometastases in sentinel node impact on
prognosis?
Maria Teresa Ionta Oncologia Medica 2
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In patients with breast cancer, nodal metastasis
in the axillary lymph nodes has historically
been considered the most important prognostic
factor
Identi?cation and early treatment of regional
lymph node metastasis in patient with invasive
breast cancer is thought to be important from a
clinical management standpoint. Improve
regional control and survival. Prognostic and
influence the choice of adjuvant systemic therapy
and RT.
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Surveillance, Epidemiology and Results (SEER),
Program of the National Cancer Institute
C.L. Carter Cancer 1989
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Relation between Primary Tumor and Lymph-Nodes
status
pT LN
pTi mic 10
pT1a 9-13
pT1b 13-19
pT1c 26-29
pT2 3 cm 39-50
pT2gt 3 cm 48-59
pT3 71-80
pT4 80-100
Adapted by Bevilacqua J L B et al JCO 2007
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C.L. Carter Cancer 1989
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C.L. Carter Cancer 1989
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C.L. Carter Cancer 1989
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DFS
OS
Mc Cready Arch Surg 1989
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CARCINOMA DELLA MAMMELLA LOCALMENTE AVANZATO
(LABC)
pN0
pN
ROUZIER JCO 2002
Distant Disease Free Survival
Distant disease-free survival according to the
axillary nodal status after primary chemotherapy.
, No residual nodal disease ---, residual nodal
disease.
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CARCINOMA DELLA MAMMELLA LOCALMENTE AVANZATO
(LABC)
pT0 pN0
pTR pN0
pT0 pN
pTR pN
ROUZIER JCO 2002
Fig Distant disease-free survival according to
the status of both breast and axillary lymph
nodes. , Complete pathologic response ---,
residual disease in breast only , residual
disease in axilla only , residual
disease in breast and axilla.
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Axillary Lymph-Node Dissection (ALND)

• Until recently, to con?rm the status of the
  axillary nodes, routine level I and level II
  axillary lymph node dissection (ALND) has been
  performed for breast cancer patients, except for
  those with noninvasive breast cancer.

Diagnostic
Therapeutic
Prognostic
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• However, although axillary node status is an
  excellent prognostic factor,
• among the 25 to 30
• of all axillary node-negative patients
  followed-up using routine pathological
  examination with single sections and only
  hematoxylin and eosin staining (HE), have a
  relapse within 10 years.

Carter Cancer 1989 Wada Int J Clin Oncol 2008
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pLN0 true or false ??

• Breast cancer as systemic disease due to early
  tumor-cell dissemination, based on primary Tumor
  characteristics ( High risk LN neg pts)
• Methods used for the detection of metastatic
  involvement may be insuf?cient and, consequently,
  a large number of patients are understaged due
  to the missing of minimal lymph node involvement
  and thus undertreated.

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Occult Metastases

• Metastases missed by initial screening and
  identi?ed on subsequent screening.
• Metastases identi?ed through the additional
  examination of paraf?n-embedded with HE
  multisections or IHC stains.

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Detection of occult node-metastases

• Routine pathological examination for all
  dissected lymph nodes has been just a single
  section stained with HE (2 Kuijt 2005 8
  Fisher 1978)
• Multi-section and using IHC technology increase
  stage migration from pN0 to pN1mi ( up to 28 of
  cases Susnik 2004)

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Occult Metastases
Almost all () occult metastases detected by
re-examination of serial sections and/or IHC were
micrometastases or smaller, defined as
nanometastases
Wada and Imoto Int J Clin Oncol 2008
() LN macrometastases 6 Tan JCO 2008
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Definition of Micrometastases
-A micrometastasis is a tumor deposit, usually
seen on Hematoxylin and Eosin (HE) staining,
mostly with multi- section method, that is
between 0.2 and 2 mm in diameter. Such nodes are
designated as pN1mi -Isolated tumor cells
(ITC), (nanometastases), are defined as single
cells or small groups of cells with a maximal
diameter of 0.2 mm, usually detected only by
immunohistochemistry. Such nodes are designated
as pN0(i) -No detectable tumor cells are
designated as pNo(i-)
6th edition of the American Joint Committee
onCancer (AJCC) Staging Manual Singletary JCO
2002 Surg Clin North Am 2003 Ca Cancer J Clin
2006
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Occult Micro-Metastases after complete ALND
and prognosis
Median 12 (7-23)
Charles E. Cox, Cancer Control 1999
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Occult Micro-Metastases after complete ALND
and prognosis
9
14,5
17
2,0
28
25
Median 14,5 (2-28)
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Lancet 1990
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• Axillary Lymph Node Nanometastases Are Prognostic
  Factors for Disease-Free Survival and Metastatic
  Relapse in Breast Cancer Patients. Alberti et al
  SABCS 2006 abstract 25
• Querzoli P, et al. Clinical Cancer Research 2006
  6696 6701
• 702 consecutive patients with 8 years of median
  follow-up were studied. To maximize chances of
  detecting micromets and nanometastases
  whole-axilla dissections were analyzed (
  retrospective analysis).
• The hazard ratio for all adverse events pN0(i)
  versus pN0(i-) was 2.51 (p 0.00019). Hazards of
  pN1mi and pN0(i) cases were not significantly
  different .

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Querzoli, P. et al. Clin Cancer Res
2006126696-6701
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Node-Micrometastases and Prognosis

• Among the patients without adjuvant systemic
  treatment, patients with micrometastases had a
  signi?cantly higher risk of dying as compared to
  patients with node-negative breast cancer (HR,
  1.51 95 CI, 1.112.06 P 0.009)

Kuijt Eur J Surg Oncol 2005
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The prognostic significance of axillary
lymph-node micrometastases in breast cancer
patients G.P. Kuijt EJSO 2005
This teaches us to be liberal in treating women
with micrometastatic breast cancer adjuvantly
because, as this study shows, in the past we have
underestimated the importance of axillary
micrometastasis
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. Disease-free survival in breast cancer patients
who were node-negative on conventional
histopathology and received no systemic therapy,
based on pathologic reassessment with current
MSKCC SLN methodology
Assessment
10-year DFS (95 CI)
p value
368 pts
IHC-/HE- (n 285) 83 (7887) lt.0001
IHC/HE- (n 33) 71 (6085)
IHC/HE (n 50) 50 (3571)
23 occult micrometastases 23 occult micrometastases 23 occult micrometastases
MSKCC, Memorial Sloan-Kettering Cancer Center SLN, sentinel lymph node DFS, disease-free survival IHC, immunochistochemistry HE, hematoxylin and eosin. MSKCC, Memorial Sloan-Kettering Cancer Center SLN, sentinel lymph node DFS, disease-free survival IHC, immunochistochemistry HE, hematoxylin and eosin. MSKCC, Memorial Sloan-Kettering Cancer Center SLN, sentinel lymph node DFS, disease-free survival IHC, immunochistochemistry HE, hematoxylin and eosin.
Adapted from Tan LK et al. JCO 2008 Adapted from Tan LK et al. JCO 2008 Adapted from Tan LK et al. JCO 2008
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Association of clinicopathological features with
distant metastases
GRADING G3 vs G1/2 p 0.01 LVI
/- p 0.001 Tumor size (cm)
lt1 gt1 p 0.01
Adapted from Tan LK et al. JCO 2008
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Occult Micrometastases in Axillary Lymph Nodes
PredictSubsequent Distant Metastases in Stage I
Breast CancerA Case-Control Study with 15-Year
Follow-Up

• The results were clear 33 (16/48) of the
  patients who ultimately developed metastases had
  occult disease in their lymph nodes compared to
  10 (5/48) who did not.
• Difference was significant only for pN1mic
• No patient had adjuvant therapy

Susnik Ann Surg Oncol 2004
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Association of clinicopathological features with
distant metastases
GRADING G3 vs G1/2 p 0.05 LVI
/- p 0.045 MI
H/L p 0.001 ITC vs none
p 0.31 MM vs none
p 0.004
Susnik Ann Surg Oncol 2004
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Occult Micrometastases in Axillary Lymph Nodes
PredictSubsequent Distant Metastases in Stage I
Breast CancerA Case-Control Study with 15-Year
Follow-Up
Finally, the association of nodal
micrometastases with subsequent occurrence of
distant metastases suggests that the presence of
nodal micrometastases may justify adjuvant
systemic treatment. This is especially important
in the group of patients with small (T1) tumors,
for whom the prognosis is generally good and, in
the current treatment schemes, are considered
candidates for the omission of systemic
treatment.
Susnik Ann Surg Oncol 2004
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Controversial findings
Biological Significance of Occult Micrometastases
in Histologically Negative Axillary Lymph Nodes
in Breast Cancer Patients Using the Recent
American Joint Committee on Cancer Breast Cancer
Staging System
H J Kahn The Breast Journal 2006
Kahn et al. suggest that breast cancer patients
with occult micrometastases (not included in
macrometastasis) in axillary lymph nodes have a
prognosis similar to those with no
micrometastases in a median 8-year follow-up.
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Occult Micro-Metastases after complete ALND and
prognosis

• The studies that showed survival differences had
  larger patient population , a relative long
  follow-up (4-25 years), or the detection of
  occult LN microm by MS and or IHC.
• The prognosis of breast cancer patients with
  micrometastases should not be considered the same
  as that of truly node-negative patients.
• Such minimal lymph node involvement cannot be
  safely overlooked.
• Patients with micrometastases should receive some
  adjuvant systemic therapy

Wada and Imoto Int J Clin Oncol 2008
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SNB ERA
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SNB ERA

• Accordingly, in developed countries, SNB has
  become an acceptable alternative to ALND for
  women with clinically node-negative early-stage
  breast cancer. The American Society of Clinical
  Oncology (ASCO), in a special article, has
  recommended SNB for patients with early-stage
  breast cancer this has been welcomed by breast
  surgery teams who already use the technique.

Lyman JCO 2005 ASCO 2005 Recommendations
38

• Serial sectioning and the use of
  immunohistochemical staining (IHC) increase the
  yield, but the methods cannot be applied to all
  dissected axillary nodes because they are too
  labor-intensive and expensive for routine use.

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Detection of the sentinel lymph node in breast
cancer Santosh K. Somasundaram Br Med Bull Ad
2008
Highest identification rates and lowest false
negative rates are achieved by using the
combined blue dye and radiocolloid technique
with pre-operative imaging
using a gamma camera
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Median SNs detected 2 ( range 1-5)
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Original sentinel node biopsies performed between
1994 and 2004 Single pathologist reviewed slides
from nearly 7000 patients
Characteristic N0(i-)(n 2762) N0(i)(n 153) N1Mi(n 132)
Mean age, yrs (range) 59 (20-94) 58 (33-86) 57 (26-90)
Mean tumor dimension, cm 1.5 1.7 1.8
Tumor type,      
Ductal only 77 76 75
Lobular only 9 17 12
Mixed/other 14 7 13
Tumor grade,      
1 17 26 23
2 28 40 42
3 19 22 27
Lymphovascular invasion, 13 50 55
Treatments received,      
Chemotherapy 23 42 48
Hormonal 38 45 36
Mean follow-up, yrs (range) 2.3 (0-18) 1.9 (0-7) 1.9 (0-9)
Cox SABCS 2005
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SNB POSITIVE

• In 3266 of patients with positive SLNs, the
  SLN is the sole site of regional node metastasis.
• In 70-80 of patients with SLNs micr, the SLN is
  the sole site of regional node metastasis
• The risk of nonSLN metastasis is related to the
  size of disease in the SLN

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Occurrence axilla after ve SN (3-4 ys) FU

• Studies 25
• Patients 8.687
• Occurences (relapses) 31
• Risk 0.36
• Range
  0-1,4
• After ALND
• Risk axillary relapse 0.8 2.3

Adapted by Cserni Br J Cancer 2004
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Correlation between SLN and Non-SLN
After ALNDNon- SN
SLNB neg SN0(i-) 60-70
4-13
13-22 microm
SN1mic
18-59 (med 40)
SLNB pos 21-47
9 nanom
SN0(i)
SN1macro
18
45-79
Adapted by Cserni Br J Cancer 2004
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Sentinel node procedure

• What can one expect from this diagnostic tool?
• Does it provide additional prognostic information
  to help choose appropriate adjuvant systemic
  therapy or RT?
• Does it determine whether the axilla should be
  treated electively?

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Sentinel Lymph-Node Biopsy and Complete Axillary
Dissection in Node-Negative Breast Cancer
Patients Yeld Similar Survival Outcomes Vero
nesi U, Paganelli G, Viale G, et al.
Sentinel-lymph-node biopsy as a staging procedure
in breast cancer update of a randomised
controlled study. Lancet Oncology 2006 7
98390. Cox C, White L, Allred N, et al.
Survival Outcomes in Node-Negative Breast Cancer
Patients Evaluated With Complete Axillary Node
Dissection Versus Sentinel Lymph Node Biopsy.
Annals of Surgical Oncology . 2006 13708-711.
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Sentinel-lymph-node biopsy as a staging procedure
in breast cancer update of a randomised
controlled study Umberto Veronesi, Lancet
Oncology 2006
58
Imoto S Prognosis of breast cancer patients
treated with sentinel node
biopsy in Japan. Jpn J Clin Oncol (2004)
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Sentinel lymph node biopsy is associated with
significantly improved survival compared to level
Iand II axillary lymph node dissection in
node-negative breast cancer patients.
355 node negative patients with early stage
breast cancer (pT1 und pT2 lt3cm, pN0/pNSN0)
Patients underwent either ALND (n178) in the
years 1990-1997 or a SLN biopsy (n177) in
1998-2004.
The median follow- up was 48.2 in the SLN group
and 120.0 months in the ALND group.
Patients in the SLN group had a significantly
better disease-free (p0.012) and overall
survival (p0.04) compared to the ALND group. In
Cox proportional hazard regression analysis, the
performed procedure (SLN compared to ALND) was
an independent predictor for improved
disease-free survival (hazard ratio 0.28, 95
confidence interval 0.11-0.75, p0.011) and
overall survival (hazard ratio 0.36, 95
confidence interval 0.14-0.89, p0.027).
Langer Journal of Clinical Oncology, 2007 ASCO
Annual Meeting Proceedings Abstr 609
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• Does the presence of micrometastases in sentinel
  axillary lymph nodes yield any tangible,
  worthwhile additional prognostic information?

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Micrometastases and Prognosis

• The substantial increase in the number of
  patients with micrometastases discovered using
  multi-section has resulted in new problems,
  especially the question of whether complete ALND
  and adjuvant systemic therapy are really required
  for these patients

Rutgers JCO 2008
67
Micrometastases and Prognosis

• Micrometastases will most likely have some role
  in in?uencing the prognosis and management of
  breast cancer.
• Ongoing randomized clinical trials will help to
  resolve questions about the treatment of
  micrometastasis over the next few years.

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TRIALS ONGOING

• the American College of Surgeons Oncology Group
  ACOSOG Z10 trial
• the American College of Surgeons Oncology Group
  ACOSOG Z11 trial
• IBCSG 23-01
• the NSABP B32
• should give us this information

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Today.
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. Technical outcomes of sentinel-lymph-node
resection and conventional axillary-lymph-node
dissection in patients with clinically
node-negative breast cancer results from the
NSABP B-32 randomised Phase III trial.
The overall accuracy of SLN biopsy was 97.1.
The false-negative rate of SLN biopsy was 9.8.
This means that SLN biopsy failed to detect
cancer in 9.8 of the women with involved lymph
nodes (as determined by ALND). False-negative
results on SLN biopsy were less common among
women who had more than one sentinel node
removed. False-negative results on SLN biopsy
were more common among women who had undergone
an excisional biopsy before their breast cancer
surgery.
Krag DN Lancet Oncology. 2007 8881-88
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Prognostic value of sentinel lymph node
involvement in patients with breast cancer.
Ninety six consecutive patients with invasive
breast cancer and tumour size less than two
centimeters by mammography, had
lymphoscintigraphy with colloidal 99Tc and
radioisotope-guided sentinel lymph node biopsy
in the University Hospital of Zaragoza from 1999
to 2005. Pathological assessment included serial
sections of the sentinel lymph node with
inmunohistochemistry for cytokeratins in
selected cases. 39 patients had histological
involvement.
Median tumour size was 20 mm (range 5-52).
Median number of resected sentinel lymph nodes
was 2 (range 1-5).
With median follow-up of 61 months, 8 relapses
have occured (0 in axilla, 2 local relapses, 6
distant metastases). Five relapses occured in 39
patients with SLN involvement (12) versus 3 in
81 patients without SLN involvement (3) (p lt
0.05).
Tobena J Clin Oncol 26 2008 Astr 22213
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Significance of sentinel lymph node
micrometastases on treatment of breast cancer.
Micrometastases in the SLN are defined as
metastases between 0.2mm and 2.0mm in size,
based on the 6th ed AJCC staging criteria, and
their clinical significance remains unknown
This study was designed to determine if patients
with micrometastatic disease in the SLN were
treated differently than patients with true N1
or greater disease
Between 1/2003 and 12/2006, 280 breast cancer
patients with positive SLN were reviewed. Of the
280 patients, 15.7 patients had micrometastases
(Group I) and 3.92 patients had metastases
lt0.2mm in the SLN (Group II). The rest (80.3)
of the patients had N1 disease or greater, with
tumor deposits gt2mm (Group III).
At our institution, ( Temple Texas )
micrometastatic disease in the SLN did not
preclude offering aggressive and standard
therapy to breast cancer patients. These
patients are treated similarly to patients with
N1 disease and are offered appropriate systemic
chemotherapy or hormonal therapy.
Sandera J Clin Oncol 26 2008 (May 20 suppl
abstr 12020)
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JWCI SN Micrometastases Trial Disease-Free
Survival

• 5-yr DFS ()
• I (Neg) 98.01
• II (IHC) 96.67
• III (Micro) 97.09
• IV (Macro) 73.56
• Mediana F/U 44 months

p0.0001
Giuliano JCO 2000
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T1N0M0
Sentinel-lymph-node biopsy as a staging procedure
in breast cancer update of a randomised
controlled study Umberto Veronesi, Lancet
Oncology 2006
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Sentinel-lymph-node biopsy as a staging procedure
in breast cancer update of a randomised
controlled study Umberto Veronesi, Lancet
Oncology 2006
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Significance of sentinel lymph node
micrometastasis on survival for patients with
invasive breast cancer
Overall survival at 2 years follow-up Stage
T1/T2 N0(i) had same survival than N0(i-) p
0.21/0.98 Among sentinel stage N0(i-), higher
T(T3) stage correlates with worse survival (P
.008) Stage T1 N1Mi predicted lower survival
than N0(i-) p 0.04 Survival for T2 N1Mi
stage not significantly different from that for
T2 N0(i-) stage
Cox C Annual San Antonio Breast Cancer
Symposium 2005 .
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Cox C Annual San Antonio Breast Cancer
Symposium 2005
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Cox C Annual San Antonio Breast Cancer
Symposium 2005
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Cox C Annual San Antonio Breast Cancer
Symposium 2005
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Micrometastases and Prognosis

• A number of studies suggest that such
  micrometastases do not independently in?uence
  overall survival when compared with tumor size
  and grade.
• Furthermore, in many patients, the need for
  adjuvant systemic treatment can be determined on
  the basis of primary tumor characteristics,
  whichmay, at times, provide stronger prognostic
  value than nodal status.

Rutgers JCO 2008
84
Micrometastases so, what to do?

• Micrometastases lt0.2 mm can be safely ignored
• Micrometastases 0.2 2 mm
• ALND
• - if non-SN -ve consider N0 and Adjuvant
• Rx on basis of primary tumor prognostic
• features.
• - if non-SN ve N1 disease

E. Rutgers SABCS 2006